The insulin-like growth factor-I receptor (IGF-IR) and its ligands (IGF-I and IGF-II) have been implicated in a variety of physiologic processes and in pathologic conditions such as cancer (see, for example, Pollack et al., Nat Rev Cancer, 2008. 8(12): p. 915-28). Although the role of the IGF system in cancer has been recognized many years ago, it is not until recently that the system's components have been targeted and shown to affect cell transformation, proliferation, survival, motility, and migration in tissue cultures and in mouse models of cancer (see, for example, Wang et al., Curr Cancer Drug Targets, 2002. 2(3): p. 191-207). The IGF-mediated signaling is initiated by binding of either IGF-I or IGF-II to their receptor (IGF-IR). Then phosphorylated IGF-IR recruits adaptor proteins, such as insulin receptor substrate (IRS) 1, IRS2 and Src-Homology Collagen (SHC) (Feng et al., Curr Opin Drug Discov Devel, 2008. 11(2): p. 178-85) Mechanistic studies have shown that ligand mediates the stimulation of IGF-IR, inducing receptor clustering and autophosphorylation followed by transphosphorylation of the β subunits (Hernandez-Sanchez et al., J Biol Chem, 1995. 270(49): p. 29176-81). The phosphorylation of IRS1 regulates the activity of phosphoinositide 3-kinase and protein kinase B (also known as Akt) and triggers transcription factors which control the expression of many genes that are important for cell proliferation and growth (Foulstone et al., J Pathol, 2005. 205(2): p. 145-53). Numerous studies demonstrated that IGF-IR is expressed in a broad panel of tumors, suggesting that inhibition of IGF-IR signaling may have both proapoptotic and antiproliferative consequences (Zha et al., Mol Cancer Ther., 2009. 8(8): p. 2110-21). Thus, it has been proposed that modulation of the activity of the IGF system could add to the arsenal of anticancer therapeutic approaches (Feng et al., Mol. Cancer. Ther., 2006. 5(1): p. 114-20). A number of epidemiologic studies have shown consistently that high circulating levels of a potent mitogen, insulin-like growth factor (IGF)-I, are associated with increased risk for several common cancers, including those of the breast, prostate, lung, and colorectum. The level of IGF-binding protein (IGFBP)-3, a major IGF-I-binding protein in serum that, in most situations, suppresses the mitogenic action of IGF-I, is inversely associated with the risk of these cancers.
There is increasing epidemiological evidence to link elevated plasma IGF-I level with prostate, breast, and colon cancer risk. Breast cancer tissues from patients exhibit higher IGFR1 expression than adjacent normal tissue, suggesting a link between IGFR1 and breast epithelial cell transformation. It has been reported that the transformation capacity of tumor cells is attenuated when IGFR1 is inhibited using an antisense strategy, neutralizing antibody (anti-IR3 or anti-IGF-I) or dominant negative truncation of the receptor (see Hailey, J. et al, Molecular Cancer Therapeutics 1: 1349-1353, 2002; Maloney E. K., et al, Cancer Res. 63: 5073-5083, 2003; Burtrum D., et al, Cancer Res., 63: 8912-8921, 2003; u et al., J. Biol. Chem. 279: 2856-2865, 2004; Miyamoto et al., Clin. Cancer Res. 11: 3494-3502, 2005; Goya et al., Cancer Research 64: 6252-6258, 2004). However, a need exists in the art for improved multi-target therapies to treat neoplastic disease and metastatic cancers.